Friday, December 28, 2012

Science Round-Up Seconds: 8 Nootropics to Combat Stroke, Alheimer's & Co and Boost Cognitive Performance. Plus: 7 Rarely Thought of Side Effects of High Dose Glutamine.

Effects of infusion times on phenol content of black tea (Ramalho. 2012)
If you have already listened to the podcast of yesterday's Science Round-Up on the Super Human Radio Website (click here if you haven't and wan't to know what the following is all about), I suppose you will not mind that I compiled some of the complex information about "optimal" tea brewing in the illustration to the right (based on Ramalho. 2012). The colored arrows indicate the time-points at which the given compounds in the tea achieved peak values. The exact time point is also given in minutes, so that a 9' in front of the green caffeine and on the left to the green arrow pointing at the 9 min point tells you "it took 9 minutes for the caffeine content to reach it's maximum in the British tea". The graph in the background shows the catechin concentration depending on the infusion time.

Cholinergenic nootropics - What a recent review says

I guess some of you will probably have heard about piracetam or lecithine as purported enhancers of cognitive function. According to a recent review in the Journal of Experimental Pharmacology those two are yet not the most prosing agents:
    Eggs are rich in choline which is an essential nutrient and was abundant in the classic BB diets (rear more)
  • Piracetam: no cerebroprotective effects in patients who have open heart surgery, but does help on non-open cardiopulmonary bypass surgery (Holinski. 2008), beneficial effects in response to cerbrovascular and cognitive disorders traumatic origin (Malykh. 2010), intravenous piracetam can prevent cognitive deficits in response to anesthesia (Fesenko. 2009)
  • Lecitin: does not improve cognitive deficits in patients (Amenta. 2011; Parnetti. 2007)
More promising "nootropics" - specifically in view of what most people do actually expect, when they buy such products.
  • Oxiracetam: improves cognitive performance except for patients with dementia (Malykh. 2010)
  • Citocoline: general neuroprotective effects (Alvares-Sabin. 2011), improvements in cognitive performance in healthy and patients and patients with dementia (Secades. 2010), helps with cognitive dysfunction in Parkinson's (Vale. 2008), helps with cognitive function in dementia of neurodegenerative and vascular origin (Parnetti. 2007), prevents cognitive decline after a stroke (Alvarez. 2011), improves recovery after stroke (Garcia-Cobos. 2010) 
  • Cerebrolysine: produces signifant cognitive improvements in vascular dementia (Guekht. 2011), effective for both cognitive function and behavioral symptoms in Alzheimer's (Alvarez. 2011), promising results in patients with Alzheimer's (Plosker. 2009)
And a couple of things you would not usually associate with nootropics:
  • Suggested read: Amino Acids for Super Humans on the effects and differences between the various forms of carnitine (read more).
    Acetyl-L-carnitine: improves cognitive performance in patients with encephalopathy, decreases anxiety and increases general energy and wellness, as well as fatigue and age-related cognitive deficits (Malaguernera. 2008, Liu. 2008),can reduce or block neuronal death in neurodegenerative diseases (Manusco. 2007), helps ammeliorate hyperammonemia (Cagnon. 2007)
  • Saffron extract: beneficial effects in mild to modest Alzheimer's  (Akhondzadeh. 2010)
  • DHA (fish oil): positive effects on verbal recognition memory in old subjects (Yurko-Mauro. 2010)
Interestingly, the most profound effects appear to be brought about by acetyl-l-carnitine. In that it's worth mentioning that the benefits could still be related to cholinergic mechanisms, since it has long been known that ALCAR can increase the expression of choline acetyltransferase activity in the central nervous system (Taglialatela. 1994). And the latter is, as the name implies, necessary to form the neurotransmitter acetylcholine .

Glutamine probably not suitable for chronic high dose supplementation

Czech scientists warn about the risks of chronic high dose glutamine supplementation. I know that many of you are still too bamboozeled by the "protein for everything and let the liver take care of any glucose demands I may have" theory, of which you could probably argue that it is the bastard child of the standard BB diet with low carb. Maybe the following recently published paper by a scientist from the Charles University in Prague can help cure this "disease" (and your cognitive problems, fatigue and brainfog).

According to Holecek, the chronic ingestion of glutamine / glutamine enriched diets in can lead to...
Figure 1: In the presence of high amounts of glutamine outside of the cell, the glutamine synthesis (GLN) and with it the ammonia detoxification from muscle tissue sucks (Holecek. 2012).
"(1) Alterations in amino acid transport-as GLN shares the transporters with other amino acids, enhanced GLN intake may impair amino acid distribution among tissues and their absorption in the gut and kidneys.

(2) Alterations in GLN metabolism-GLN supplementation may impair synthesis of endogenous GLN and enhance glutamate and ammonia production.

(3) Alterations in ammonia transport-GLN supplementation may impair ammonia detoxification and negatively affect the role of GLN as the carrier of ammonia among tissues.

(4) Abnormalities in aminoacidemia-increased plasma levels of GLN, glutamate, citrulline, ornithine, arginine, and histidine and decreased levels of valine, leucine, isoleucine, glycine, threonine, serine, and proline are reported.

(5) Alterations in immune system-as GLN has immunomodulating properties, the effect of chronic GLN consumption on the immune system needs to be assessed.

(6) Effect on tumor growth-it should be elucidated whether chronic intake of GLN increases the risk of cancer.

(7) Effect of the withdrawal of GLN supplementation-due to the adaptive response of the organism to enhanced GLN consumption, the withdrawal of GLN may enhance the risk of health problems resulting from GLN deficiency." (Holecek. 2012)
Remember the post on the ammonia induced peripheral and central fatigue with high dose chronic BCAAs supplementation?
In view of the fact that some people consumer up to 40g of glutamine regularly, Holecek demands that "long-term studies should be performed" to test the side effects and evaluate whether there is any benefit at all to justify chronic consumption of a GLN-enriched diet.

So, relying on glutamine instead of carbs, as smart as this idea appears to be in the current carbophobia, could actually make you stupid due to the disruption of the intracellular ammonia detoxification, which is not a problem in muscle only, but also in the brain.

In the end, what we are seeing here is just another instance of a disruption in the natural balance of things. Ornithine, citrulline and arginine, for example are involved in the detoxification of ammonia via the urea cycle. They are however not the only bottleneck to the system.

Obviously your liver and kidneys will have to handle the clearance. People with liver problems (or persons taking "supplements" or NSAIDs that may impair the liver function) are therefore particularly prone to hyperammonemic encephalopathy (Kanamori. 1996; Lemberg. 2009)

Bottom line: Glutamine, just like everything else, in moderation and by no means so much that your body runs on glutamine as fuel. Aside from the mentioned amino acids that help the clearance of ammonia from the blood stream, taurine appears to exert a direct protective affect in the brain (Chepkova. 2006), and lactulose (a fermentable carbohydrate) can reduce the ammonia influx from ammonia producing bacteria in the gut (Vince. 1980). So if you want to wear a helmet when you bang your head against the wall, these would be suggested "take supplement B in order to counter the side effects of supplement A" - side effects of a supplement you would not even have to take, by the way (100% bro-logic ;-)

  • Amenta F, Carotenuto A, Fasanaro G, Lanari A, Rea R, Traini E. Preliminary results of Ascomalva trial on the association of donepezil and choline alphoscerate in Alzheimer’s disease with associated cere-brovascular injury. G Gerontol. 2011;59:89–9.
  • Akhondzadeh S, Shaf iee Sabet M, Harirchian MH, Togha M. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativusin the treatment of mild-to-moderate Alzheimer’s disease. Psychopharmacology (Berl). 2010;207:637–643.
  • Alvarez XA, Cacabelos R, Sampedro C, et al. Efficacy and safety of cerebrolysin in moderate to moderately severe Alzheimer’s disease: results of a randomized, double-blind, controlled trial investigating three dosages of cerebrolysin. Eur J Neurol. 2011;18: 59–68.
  • Alvarez-Sabín J, Román GC. Citicoline in vascular cognitive impair-ment and vascular dementia after stroke. Stroke. 2011;42(Suppl 1): S40–S43.
  • Cagnon L, Braissant O. Hyperammonemia-induced toxicity for the devel-oping central nervous system. Brain Res Rev. 2007;56:183–197.
  • Chepkova AN, Sergeeva OA, Haas HL. Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment. Neurobiol Dis. 2006 Sep;23(3):512-21.
  • Fesenko UA. Piracetam improves children’s memory after general anaesthesia. Anestezjol Intens Ter. 2009;41:16–21. Polish
  • García-Cobos R, Frank-García A, Gutiérrez-Fernández M, Díez-Tejedor E. Citicoline, use in cognitive decline: vascular and degenerative. J Neurol Sci. 2010;299:188–192.
  • Guekht AB, Moessler H, Novak PH, Gusev EI; Cerebrolysin Investigators. Cerebrolysin in vascular dementia: improvement of clinical outcome in a randomized, double-blind, placebo-controlled multicenter trial. J Stroke Cerebrovasc Dis. 2011;20:310–318. 
  • Holecek M. Side Effects of Long-term Glutamine Supplementation. JPEN J Parenter Enteral Nutr. 2012 Sep 18.
  • Holinski S, Claus B, Alaaraj N, et al. Cerebroprotective effect of piracetam in patients undergoing coronary bypass surgery. Med Sci Monit. 2008;14:153–15.
  • Kanamori K, Ross BD, Chung JC, Kuo EL. Severity of hyperammonemic encephalopathy correlates with brain ammonia level and saturation of glutamine synthetase in vivo. J Neurochem. 1996 Oct;67(4):1584-94.
  • Lemberg A, Fernández MA. Hepatic encephalopathy, ammonia, glutamate, glutamine and oxidative stress. Ann Hepatol. 2009 Apr-Jun;8(2):95-102.
  • Liu J. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res. 2008;33:194–203.
  • Mancuso C, Bates TE, Butterfield DA, et al. Natural antioxidants in Alzheimer’s disease. Expert Opin Investig Drugs. 2007;16:1921–1931.
  • Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue. Arch Gerontol Geriatr. 2008;46:181–19
  • Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl-L-carnitine treatment in minimal hepatic encephalopathy. Dig Dis Sci. 2008;53: 3018–3025
  • Malykh AG, Sadaie MR. Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders. Drugs. 2010;70:287–31
  • Pantoni L. Treatment of vascular dementia: evidence from trials with non-cholinergic drugs. J Neurol Sci. 2004;226:67–70
  • Parnetti L, Mignini F, Tomassoni D, Traini E, Amenta F.  Cholinergic precursors in the treatment of cognitive impairment of vascular origin: ineffective approaches or need for re-evaluation? J Neurol Sci. 2007;257:264–269.
  • Ramalho SA, Nigam N, Oliveira GB, Alves de Oliveira P, Matos Silva TO, Passos dos Santos AG, Narain N. Effect of infusion time on phenolic compounds and caffeine content in black tea  Food Research International; 13 December 2012 [ahead of print]
  • Secades JJ. Citicoline: pharmacological and clinical review. Rev Neurol. 2010;52 Suppl 2:S1–S62.
  • Vale S. Current management of the cognitive dysfunction in Parkinson’s disease: how far have we come? Exp Biol Med (Maywood). 2008;233:941–951.
  • Vince AJ, Burridge SM. Ammonia production by intestinal bacteria: the effects of lactose, lactulose and glucose. J Med Microbiol. 1980 May;13(2):177-91.
  • Yurko-Mauro K. Cognitive and cardiovascular benefits of docosahexaenoic acid in aging and cognitive decline. Curr Alzheimer Res. 2010;7:190–196.


  1. "Polish scientists... a scientist from the Charles University in Prague"
    If it's a University in Prague than they are Czech, not Polish, scientists.
    Apart from that: thanks for the great job and happy year!

    1. thanks, I don't know where I left my brain; too much glutamine maybe ;-)

      and additional thank you for the new year's wishes and the general compliment

  2. Doesn't alcar have a negative effect on thyroid action?

    1. maybe you are mixing ALCAR and ALA = alpha lipoic acid

      Arzneimittelforschung. 1991 Dec;41(12):1294-8.
      Effect of alpha-lipoic acid on the peripheral conversion of thyroxine to triiodothyronine and on serum lipid-, protein- and glucose levels.

      Segermann J, Hotze A, Ulrich H, Rao GS.


      Institute of Clinical Biochemistry, University of Bonn, Fed. Rep. of Germany.

      The influence of alpha-lipoic acid (LA, thioctic acid, CAS 62-46-4) on thyroid hormone metabolism and serum lipid-, protein- and glucose levels was investigated. In the first setup of experiments administration of LA together with thyroxine (T4) for 9 days suppressed the T4 induced increase of T3 generation by 56%. This suppression was similar to that affected by 6-propylthiouracil (54%). LA or T4 alone did not affect the cholesterol level, but together they led to a reduction. LA decreased the triglyceride level by 45%; the decrease induced by T4 or LA plus T4 was not significant. Total protein and albumin levels decreased by LA plus T4 treatment when compared to the LA control. The slight increase in glucose level by LA or T4 alone was not observed when they were administered together. In the second setup of experiments the administration of T4 for 22 days increased the serum T3 level 3-fold. When LA was combined with T4 and the treatment continued, the T3 production decreased by 22%. T4 reduced cholesterol level by 30%, and LA plus T4 further reduced it by 47%. The triglycerides were not affected. A moderate decrease in total protein was observed after treatment with T4 plus LA; T4 and LA plus T4 decreased the albumin level. The decrease in serum glucose by T4 recovers by LA treatment. These results demonstrate that LA interferes with the production of T3 from T4 when it is co-administered with T4.

      PMID: 1815532

      Alcar on the other hand does not mess with thyroid function

      To gain insight into the hormonal modifications induced by ALCAR supplementation, we measured serum levels of free T3 and leptin, which are involved in the regulation of nutrient metabolism (12–14). ALCAR treatment neither affected serum free T3 levels in young rats nor restored the age-dependent decline in old rats (Fig. 3A).

      But builds muscle in old rats (who by the way usually have low IGF-1, plus there is human data showing that this effect translates to human beings, as well) and helps young ones to stay lean (see

    2. Hi Prof,

      Thanks for the quick reply, your advice is always appreciated. Actually it was alcar I had read about interfering with thyroid and not ALA. Mainly just peoples comments in forums, but for your information / interest I had a quick look and found these in pubmed:

      But - as you have often pointed out, abstracts don't always give the full story, not that even the abstracts mean that much sense to me!!

    3. I took a peak at the studies. All are related to a NORMALIZATION of thyroid function in hypothyroidism. Look, if you take aspirin because you have a fever, this will decrease your body temp. Can you conclude that it will cool you down till you die if you take aspirin, when you are not feverish? I would not think so.

    4. Thanks prof. Once again i appreciate you taking the time to answer questions. I'll be adding a small amount back in my morning supps again!

  3. Carnitine intake increases IGF-1, which is linked with cancer and aging. As does high protein intake. What is your view on IGF-1. I know it is important for muscle growth.

    Here is the link on protein - Comparative and meta-analytic insights into life extension via dietary restriction. f100

    1. Nonsense. Really. All of it, including protein and cancer & aging (start here:

    2. IGF-1 is important for healthy aging, without it you end up having brittle bones (see

      honestly, this type of longevity research telling you to eat less (better nothing or only salad) and f**** up your metabolism so that you live like a tortoise (both as long, as well as as miserably and laughably "slow") is bogus.

      also check out

      which lists

      neural protection
      cardio protection
      insulin sensitiyation
      protection from osteoporosis

      as longevity benefits of IGF-1 and ONLY ONE THING namely cancer as a downside (and don't tell me about receptor knockout rodents / these are only partial knockout, anyway) - now who gets cancer? Right those who are insulin intolerant, what else do they get? Right, osteoporosis, heart attacks and Alzheimer's so, if you got high IGF1 because you got insulin resistance and your body is trying to compensate for that by more IGF-1, this could be an issue, but if you look up "ALCAR and longevity" you will be hard pressed to find anything but benefits; why? Because ALCAR ran resensitize your cells for glucose uptakte, reduces the ROS generation by optmizing mitochondrial function etc.

    3. Kiefer, that link you posted, correctly concluded that CR seems to work only on models. I suspect that its because of high carb / artificial diets animals are usually put on, combined with stress of laboratory life.

  4. Dr. Andro what would you recommend as a "study stack" to improve and optimize cognitive function and memory formation?

    1. Here it is:

    2. the stack you mentioned looks good, Majkinetor. The only problem I see is that having so many ingredients makes it literally impossible to determine what works and even worse what may be giving you a headache.

      There are in fact tons of natural nootropics you can chose from: Ginkgo biloba, Rhodiola rosea, Siberian ginseng, Brahmi rasayana, Bacopa monniera, Lycoris radiata, Sutherlandia frutescens, Mucuna pruriens, Butea frondosa, St John’s Wort, Arecholine, galanthamine, huperzine A, vinpocetine, Grape seed extract, Caffeine, Curcumin and many more...

      I would be reluctant to recommend any of them, but caffeine, grape seed and curcumin are probably the safest and most efficient ones for long-term ingestion (also with other beneficial health effects)

      what I can wholeheartedly recommend is getting your 8h of sleep in pitch black darkness (and with ear-plugs if you live anywhere where you would otherwise wake up) IN SYNC with your biorhythm (cf.

      working out regularly and going out for a walk EVERY DAY and do whatever it takes to keep your blood sugar stable

    3. Thats all nice, but 'study stack' usually requires urgent results. People in my surroundings ask me that stuff few weeks before the exam. GetSmart can deliver in such short time. I really don't care which one did it, as the one doesn't need to take that complex forever. Several people I know take it 1-2 times per year in specific situations.

      I mentioned it as its something I know people tried and doesn't seem to have any noticeable side effects (I stopped personally after 10 caps because I couldn't stand strong chemistry odor of my urine and sweat, but others thought its either trivial problem or non existent).

      So there is certainly no harm to try it, just don't abuse it for the time being.

      Also, the one can choose some subset of those chemicals - for instance some racetam mix + Picamilon + Idebenone (CoQ10) + Choline (or better, 2-4 egg yolks/day depeinding on how much of the cholinergic stuff you take, or your head starts to hurt) and skip the others. In many countries those could be found all. around

  5. Piracetam works best on longer run and if combined with Lecithin. Taking single 12g dose isn't very meaningful IMO relating to cognition. Perhaps its OK only as antiplatelete/antihypertensive agent for cardivascular patients but for any neurological effects it needs to be taken for at least 3 months and longer. Many people take it for years, with some on/off periods.

    The best thing about piracetam is that its almost completely safe - its vitamin like substance - and that, for many people I know it influences mood and sleep a lot. I had trouble to wake up since I was 16 up to my 30ies, 10-12 hour sleep was a norm. On piracetam I can sleep 5 hours a day and be productive. My side effect is myokimia, so I must keep the dose low (~1g).

    The effect on mood and thought clarity with larger doses 5-10g is obvious, and everybody notice it.

    The benefit of cells being able to survive hypoxic conditions is something that needs to be underlined. Combined with proper other nootropics like Idebenone it probably makes one highly resistant to such stress (which happens on microlevel all the time)

    1. Thanks for all the suggestions!
      Do you think the effects of Aniracetam would be superior to Piracetam since it's fat soluble?

    2. accoriding to this study the answer is yes =>

      "At 60 min, scopolamine produced marked and significant decrements in all of the measures of memory and information processing. Aniracetam 1500 mg was able to significantly antagonize decrements on both memory and information processing tasks. The other active treatments [injection of low dose aniracetam or high(er) dose piracetam] also produced significant effects, but for two these were equal to, and for two slightly above, the number which may have occurred by chance, and thus were questionable."

      On short it should not be a problem. In the long time I am usually skeptic with fat soluble drugs, because most share the ability of being stored.

  6. learning_to_lift_weightsDecember 28, 2012 at 8:38 PM

    Hi Prof., about glutamine, how much is too much & how less is beneficial (if there is any)?

    Thanks for the great work. :-)

    1. I guess the benefits depend largely on your basic protein intake and sources.

      Most benefits have been observed in "in intensive care patients, patients with human immunodeficiency virus (HIV), patients with muscle-wasting disorders, cancer patients undergoing chemotherapy, and patients with inflammatory bowel diseases"

      "The beneficial effects of GLN provision may result simply from correction of disadvantages resulting from its deficiency. From this point of view, it is hard to believe that the positive effects of GLN supplementation observed in patients with GLN deficiency appear also in those with GLN stores in physiological ranges."

      it should not be underestimated that ATP is required for the ammonia detoxification that involves glutamate + ammonia + ATP.

      In essence I don't think supplementing with <5g without any of the afore-cited pathologies makes sense. Still people with adequate liver function are not so much at risk if they took say 10g per day - more than that does not seem to bring any benefits (in athletes it has even been established that it is not ergogenic), so why bother with taking more supplemental glutamine?

    2. learning_to_lift_weightsDecember 29, 2012 at 12:24 PM

      Thank you very much, Prof.

  7. Very nice post. I completely forgot about 50g of sulbuthiamine I have laying around unpacked. Started today, we will see.

    1. I think you meant sulbutiamine? I love the stuff. I just returned to it a week ago at about 1 gram/day 1x. I know some consider this a high-dose but I like the stimulating effect that seems to not be taxing to the adrenal glands. On the other hand, I might be getting a mild headache and fatigue with that dose.

  8. Dear Prof Andro, WikiP points out, "When taken as a supplement citicoline is hydrolyzed into choline and cytidine in the intestine. Once these cross the blood–brain barrier it is reformed into citicoline by the rate-limiting enzyme in phosphatidylcholine synthesis, CTP-phosphocholine cytidylyltransferase."

    Citicoline is a little expensive for my taste. As you suggested in another article, taking bulk choline, or eating egg yokes could provide a cheaper source of Choline. Can you suggest good sources of Cytidine, so I can metabolize my own Citicoline? I cannot seem to find Cytidine in bulk. Thank you!
    Wurtman, RJ; Regan, M; Ulus, I; Yu, L (2000 Oct 1). "Effect of oral CDP-choline on plasma choline and uridine levels in humans.". Biochemical pharmacology 60 (7): 989–92. doi:10.1016/S0006-2952(00)00436-6. PMID 10974208.

    1. you could have found the answer in the wikipedia, as well => "organ meats, Brewer's yeast, as well as pyrimidine-rich foods such as beer. During digestion, RNA-rich foods are broken-down into ribosyl pyrimidines (cytidine and uridine), which are absorbed intact.[1] In humans, dietary cytidine is converted into uridine,[2] which is probably the compound behind cytidine's metabolic effects."

  9. Thanks Adel. Brewers yeast is the only one of those foods I could be taking on a regular basis. Can you tell us anything about the proportions of brewers yeast to choline bitartrate that might be recommended to give the best results in the brain? I discovered that in Brewer's Yeast, "Purine and pyrimidine N represents a relatively constant fraction of total N, in the vicinity of 11.5%." But I could not find information about how much uridine (the likely key metabolite), is represented in the pyrimidine/purine fraction of brewer's yeast (or how much is produced upon metabolism). If we teased that information out, then should we assume a 50:50 uridine:choline ratio is optimal? Thanks! Your energy to respond intelligently to all these posts is truly amazing.

  10. Most benefits have been observed in "in intensive care patients, patients with human immunodeficiency virus (HIV), patients with muscle-wasting disorders, cancer patients undergoing chemotherapy, and patients with inflammatory bowel diseases"

    "The beneficial effects of GLN provision may result simply from correction of disadvantages resulting from its deficiency. From this point of view, it is hard to believe that the positive effects of GLN supplementation observed in patients with GLN deficiency appear also in those with GLN stores in physiological ranges."

    it should not be underestimated that ATP is required for the ammonia detoxification that involves glutamate + ammonia + ATP.
    piracetam nootropic

  11. Piracetam – one of the first nootropics discovered, it is also one of the most popular. Taken daily, the dose should be 2 to 6 grams. Reported side effects are rare, and mild.

  12. Excellent, thanks for the information. I think sunifiram should be added to this nootropic list. Please check out my blog

    Thanks :)